The hypothalamic-pituitary-adrenal HPA) axis is an important component of the stress system, which enables humans and other organisms to respond to perceived environmental threats. The most important regulators of this system are corticotropin-releasing hormone (CRH) and vasopressin (AVP). Dysregulation of the HPA axis is implicated in several chronic diseases such as depression, anorexia nervosa, obesity, alcoholism, fibromyalgia, and chronic anxiety states. The development of drugs for these disorders targeting CRH receptors is underway, though the effects of chronically blocking CRH receptors and of the development of compensatory mechanisms are unknown. The overall goal of the proposed project is to help delineate the respective roles of CRH and AVP in modulating the stress response, using the CRH deficient mouse model. The first specific aim will test the hypothesis that CRH release, brought on by stress, down-regulates its own response and upregulates the response of AVP in hypothalamic neurons. Changes in CRH, AVP, and CRH receptor expression in the hypothalamus will be examined in CRH-deficient and normal mice subjected to acute and chronic stress paradigms. The second specific aim involves the detection of c-fos expression, which has been used as a marker for neuronal activation of stress-related areas of the brain. By studying differences in c-fos expression in CRH-deficient and normal mice, the possible role of CRH in adaptation to chronic stress will be explored.